Biologists Find Roundworm Protein Similar to Human Cancer Protein

PASADENA—A team of biologists has found a striking similarity between a protein found in roundworms and a common but puzzling protein in humans that is sometimes involved in the growth of cancer. This link, reported in the August 25 issue of the journal Science, will help scientists who study human cancer genes direct their research in more promising directions.

The human protein, called CBL—pronounced "sibyl"—was discovered by Wallace Langdon of the University of Western Australia, and is important to the study of cancer in people because a mutant form of CBL promotes the growth of cancer. Scientists already knew that CBL, in either a normal or a mutant form, could be modified by the activation of any of a number of different surface receptors.

Surface receptors are the means by which cells communicate. Many different kinds of receptors sit on the surface of each cell, and each type is sensitive to a particular signaling protein. When a signaling protein meets a receptor that recognizes it, they fit together like a key in a lock, and the receptor conveys the signal to the cell's interior, where it activates a series of events.

While it is well known that CBL can promote cancer in its mutant form, no one knows what it does in its normal form. Researchers need to better understand CBL's role in a healthy cell, so they can figure out how, when it mutates, it can lead to cancer.

Here's where the roundworms come in. The nematode Caenorhabditis elegans, a microscopic roundworm commonly used in genetic research, has a surface receptor on its cells called LET-23 that is equivalent to the receptor for epidermal growth factor in humans.

LET-23 and many proteins that act as signaling proteins are well known to scientists, but Charles H. Yoon, a graduate student in the lab of Paul Sternberg, an associate professor of biology with the Howard Hughes Medical Institute at Caltech, has been studying an inhibitor protein called SLI-1. Inhibitor proteins interfere with the activation of a receptor. The SLI-1 protein is thought to inhibit the LET-23 receptor and thus inhibit signaling inside the cell.

After several years of genetic study and sequencing, Yoon found that the structure of SLI-1 is remarkably similar to a well-known human cancer protein: the puzzling CBL! Proteins are made of long strings of amino acids, and over a stretch of 390 amino acids, SLI-1 from the roundworm shares 55 percent of the same amino acids in the same order with CBL from humans.

This important link between two cancer research efforts, one in people and one in roundworms, suggests that the function of CBL in human cells, until now a mystery, may very well be the same as SLI-1 in nematodes. CBL, like SLI-1, could be an inhibitor of surface receptors' ability to convey a signal to a cell's interior.

Several labs, including Sternberg's, have found comparable similarities in the structure and function of proteins from people and roundworms in the same signaling pathway that includes CBL. (A pathway is a sequence of related signals and activity in and between cells, and this one is especially important because it also controls the activity of the RAS protein, a superstar player in the development of cancer.) But even if CBL doesn't play a role in humans exactly analogous to SLI-1's role in roundworms, this finding gives a broad hint to researchers who study human cancer genes. Now they know one of the pathways in which CBL is involved, and can begin to study CBL's role in it.

Former Caltech graduate students Junho Lee, now at UC Berkeley, and Gregg D. Jongeward, now at UC San Francisco, also contributed to this research, which was supported primarily by funding from the National Institutes of Health.